Isolators vs. Restricted Access Barrier Systems
What are isolators?
Isolators are self-contained devices that perform automated functions and provide controlled environments with little to no microorganism exposure. These isolators remove the need for human contact and are made of surfaces that can be easily decontaminated, like plastics, glass, and stainless steel. Most sterility testing that follows United States Pharmacopeia (USP) guidelines utilizes isolators. HEPA air filtration is used in isolator systems. Air filtration systems are quickly decontaminated using sterilization-in-place decontamination processes. Sterilization-in-place processes decontaminate other isolator surfaces with steam and chemical treatments to prevent microbial growth. Isolator systems are either “open” or “closed.” Closed isolators do not have a direct opening to the external environment. Instead, closed isolators use rapid-transfer ports to move materials in and out of the closed system. In contrast, open isolators allow materials to enter the isolator chamber through a defined opening protected by air overpressure. Regardless of the isolator type (i.e., open or closed), materials entering or leaving isolators are transported aseptically. As isolators eliminate direct contact between human operators and products, any aseptic manipulations within the isolator are made with half-suits. Half-suits are glove and sleeves systems that allow the operator to manipulate items within the isolator. Often either an RABS system (restricted access barrier system) or RABS isolator will be used instead of traditional isolators for medical device manufacturing. In some cases, medical isolators are required for the handling of sterile medical products in hospitals. Both isolators and RABS require ISO certifications (also known as isolator certification or RABS certification).
What are restricted access barrier systems?
Restricted access barrier systems (RABS) are a type of sterile processing environment for non-sterile and sterile manufacturing. RABS are built inside ISO 5-7 clean rooms. They provide ISO 5 unidirectional air inside the barrier and prevent contamination with an air overspill system from within the barrier. Open RABS have specialized barrier openings to enable human intervention. Closed RABS do not allow human intervention and operate with the same operator restrictions as isolators. Closed RABS operate with positive or negative pressure, similar to isolator systems. Sterile items are manipulated in RABS using glove ports. Materials are transferred aseptically without opening the system. A RABS, like other regulated cleanrooms, requires decontamination before use.
How are isolator systems designed and operated?
Isolator systems (with the exception of some medical isolators) are custom-made. The most important components for isolator design are air handling systems, material transfer areas, microbial monitoring systems, and microbial decontamination processes. While the design of the isolator is imperative to its function, so is the implementation of an appropriate training program for those that operate, monitor, and control isolator systems. Operation, monitoring, and control of medical isolators is less extensive than the manufacturing isolator systems described below.
Air Handling Systems
Isolators for sterility testing contain microbial retentive filters (i.e., HEPA filters or better). Isolators are ISO Class 5 areas. Thus, isolators must meet ISO Class 5 particulate air-quality requirements unless used for manufacturing operations that generate particulates. Isolator air systems must be capable of handling sporicidal vapors and decontamination gases within the system. Further, air systems must maintain a positive pressure gradient relative to the outside environment to prevent microbial ingress during operation or the transfer of materials into or out of the isolator system. Standard overpressure levels are twenty Pascals or more. Airflow within the isolators is either unidirectional or turbulent.
Material Transfer Areas (Ports & Doors)
Many isolators have attached decontamination systems that allow sterile media and other supplies to be transferred into the isolator system. Alternatively, rapid transfer ports (RTPs) are used to connect two isolators (the workstation and material transfer isolator). The nonsterile surfaces of the RTPs are attached using locking rings or flanges, and a compressed gasket system prevents microbial contamination through an airtight seal. RTPs quickly allow supplies to be aseptically transported through linking flanges and forming an airtight passage. A narrow band of the RTP’s gasket system provides the primary risk for microbial contamination. Thus, the exposed gasket areas are disinfected before airtight connections are made and materials transferred through the RTP. To further reduce contamination risk, gasket assemblies are regularly lubricated, and RTP gaskets are changed periodically to prevent any cut or torn gaskets from being used. Note that material transfer areas are particularly important for microbial and dust control within medical isolators.
Microbial Monitoring & Decontamination Systems
Microbial monitoring and decontamination systems assure that aseptic conditions are consistently maintained within isolator systems. Microbiological monitoring programs detect any issues with isolator system operation and contaminants within the isolator. Microbiological monitoring is a form of environmental monitoring where the internal isolator environment (e.g., surfaces, air, etc.) are regularly sampled. Traditionally, samples are taken following decontamination on the first and the last day of operation. Settling plates and contact plates may be used for sample collection. However, low-level contaminants will not be detected with these methods. Continuous nonviable particulate monitoring within the isolator’s enclosure is ideal for maintaining ISO Class 5 particulate levels.
The greatest contamination risks for isolator systems are adding supplies and samples into the enclosure and using half-suit assembly equipment. Decontamination protocols for added materials, periodic inspections of RTP gaskets, glove selection, and glove leak monitoring are all ways to prevent microbial contamination went adding materials into an isolator. Gloves made with Hypalon materials are the best for isolator systems. These gloves are resistant to punctures and the chemical sporicides used in isolator decontamination. Small glove leaks can be detected by submersing the gloves in 0.1% peptone water, filtering the solution, and plating the filtrate on growth media. Medical isolators are often much smaller than manufacturing isolators. Thus, microbial monitoring and decontamination processes for medical isolators may be similar but over a compact area.
Training Programs
Isolators (medical isolators, rabs isolators, etc.) and clean rooms require appropriate aseptic techniques to maintain product sterility and testing accuracy. Thus, aseptic technique training is needed for all isolator operators. Additionally, all training sessions and personnel evaluations related to isolator use must be documented. Regular maintenance and upkeep for ISO Class 5 certification are required for all isolator systems in service.
How are RABS designed and operated?
#1: Open RABS Operation
In RABS, incoming air passes through high-efficiency (HEPA Class H14 or better) filters and is evenly distributed by a sterile manifold. Glove ports are the only means of access to products and equipment within the RABS. Thus, aseptic transfer systems are used to move materials and products into and out of the RABS.
Glove Integrity Checks
Glove checks are part of guaranteeing RABS barrier integrity. Before use, gloves are tested for leaks and damage. Physical testing of the gloves before sterilization and mounting occurs in addition to visual glove examinations. Some RABS prefer to test mounted gloves since the entire glove assembly (including the mounting ring) can be verified when the gloves are mounted. However, testing the gloves before mounting can reduce set-up time.
Glove sterilization and installation is the second challenge facing RABS glove integrity. For installation, gloves are pre-sterilized in an autoclave, transferred into the cleanroom, and installed to the mounting ring aseptically. Glove mounting requires experience. Some operators prefer to reverse the mounting ring to aid the glove-mounting process. However, reverse mounting often requires the use of a longer glove.
Sterile Material Transfer Checks
Materials, products, and tools must be transferred in and out of the RABS sterilely. A RABS uses a double-door transfer with steam sterilizers, a transfer chamber, or a simple transfer door to move materials in and out of the barrier. Transfer chambers have interior and outer doors that interlock such that only one door can be opened at any point in time. The interior of the transfer container should be ISO category 5 for RABS. If simple transfer doors are used, they are installed below the RABS process level to reduce the impact of ambient air on the aseptic area. Closed RABS can be operated with positive pressure. However, opening the doors of a closed RABS is not allowed.
Disinfection System Checks
The sanitation of a RABS is complex, as all interior surfaces must be sanitized. Each cleaning with human operators risks contamination and the movement of low-quality outside air into the RABS. Thus, most RABS and all closed RABS have automatic clean-in-place (CIP) systems. CIP systems use steam and other sanitizing agents to clean RABS surfaces and eliminate the need for manual cleaning. CIP and sanitization system functionality is essential to RABS cleanliness for product assembly, filling, or handling.
#2: Closed RABS Operation
Closed RABS are special cases because they must meet aseptic and industrial safety requirements. As mentioned earlier, the recirculated air in a closed RABS must be prefiltered before returning to the air-recycling system. Thus, closed RABS must have protocols for contamination-free prefilter changes (i.e., bag-in-bag-out). Pressure-isolation zones and buffers protect upstream and downstream equipment from filling-area contamination. Pressure zones require specialized sealing requirements. RABS operation and design have three primary elements to ensure safe use: glove integrity checks, sterile material transfer checks, and disinfection system checks. Industrial safety requirements and product exposure limits determine the leak tightness of a closed RABS. In cases with peak sealing requirements, the requirements and costs of a RABS are the same as an isolator system.
What are the differences between isolators and RABS?
Isolators and RABS cost the same amount as RABS product exposure limits and leak tightness requirements increase. However, a RABS typically has faster startups, easier change procedures, more operational flexibility, and lower validation process costs than isolator systems. As many RABS are open RABS and involve manual cleaning procedures, the validation of cleaning systems (if CIP is not used) is more challenging for RABS than isolators. Glove handling and assembly at glove ports in RABS is also more complex due to sterility requirements. However, isolator air handling systems are far more complex and costly than RABS as the air is recirculated within these systems. Overall, isolators provide high-level aseptic manufacturing atmospheres that surpass the conditions of most isolator systems. However, isolators offer less operational flexibility and greater validation and revalidation costs than RABS.
Summary
Overall, isolators are self-contained devices that perform automated functions and provide controlled environments with little to no microorganism exposure. In contrast, restricted access barrier systems (RABS) are a type of sterile processing environment for non-sterile and sterile manufacturing. There is only one primary isolator type. However, the four types of RABS systems are open active, open passive, closed active, and closed passive systems. Closed RABS have additional aseptic and industrial safety criteria that must be met compared to open systems. The most important components for isolator design are air handling systems, material transfer areas, microbial monitoring systems, and microbial decontamination processes. In RABS systems, glove integrity checks are also critical. Comparatively, isolators provide high-level aseptic manufacturing atmospheres that surpass the conditions of most isolator systems. However, isolators offer less operational flexibility and greater validation and revalidation costs than RABS. In some cases, the sealing requirements and costs of a closed RABS are the same as an isolator system. Contract manufacturing and testing organizations use RABS and isolators for their manufacturing and testing processes. When outsourcing regulatory testing, ensure you choose a contract testing organization that can support you with appropriate equipment to test your unique medical devices or products.
Ethide Labs is a contract testing organization that specializes in Sterility Testing and Environmental Monitoring. Ethide Labs also offers Bioburden Testing, Microbiology Testing, Bacterial Endotoxin Testing, Ethylene Oxide Residual Testing, Cytotoxicity Testing & Package Integrity Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
Johannes Rauschnabel. The Advantages of Restricted-Access Barrier Systems. Pharmaceutical Technology, Volume 31, Issue 3. March 2007.
United States Pharmacopeial Convention. <1208> Sterility Testing—Validation Of Isolator Systems. Rockville, MD, USA. 2021. (USPC <1208>).
United States Pharmacopeial Convention. <1211> Sterility Assurance. Rockville, MD, USA. 2021. (USPC <1211>).
